PROJECT SUMMARY/ABSTRACT The emergence and persistence of antimicrobial resistant pathogens are a serious threat to human and animal populations worldwide. Although antimicrobial use is known to select for antimicrobial resistance (AMR), resistance often persists in the absence of antimicrobial exposure. An improved understanding of the epidemiology of AMR in natural pathogen populations is needed. However, traditional epidemiological methods are not well-suited for understanding AMR risk factors because they do not account for the ecological and evolutionary processes that confound the expected association between antimicrobial exposure and AMR. Improved epidemiological methods that incorporate ecological and evolutionary principles are necessary for providing new insights on AMR, informing more effective AMR prevention strategies, and ultimately promoting the future efficacy of antimicrobial therapies. The long-term goal of this research is to develop a quantitative framework integrating ecological and evolutionary principles with epidemiological methods to advance existing knowledge of AMR risk among human and animal populations. This proposal aims to use commensal Campylobacter coli populations in commercial swine herds as a model system to investigate the ecology, evolution, and epidemiology of AMR. Prior studies found that C. coli from pigs reared under both conventional and antibiotic-free farms were resistant to fluoroquinolone and macrolide antibiotics, which is clinically significant as these drugs are used to treat human campylobacteriosis. The proposed research will build upon this previous work and accomplish the following aims: 1) identify and quantify host exposures and microbial genotypes associated with phenotypic resistance to fluoroquinolone and macrolide drugs among commensal C. coli in swine herds using probabilistic graphical models (i.e. chain graphs), and 2) quantify selection and bacterial fitness costs of genotypes associated with fluoroquinolone- and macrolide-resistance among natural C. coli populations in presence and absence of antimicrobial use, using phylodynamic methods. The expected outcome of this research is the development of a quantitative framework that can be applied to any host-pathogen system in which AMR is a threat to elucidate drivers of AMR selection and persistence. This proposal and mentorship team will provide training critical for the applicant?s development as an independent clinician-scientist studying infectious disease epidemiology at the human-animal interface. The interdisciplinary research training plan will provide the applicant opportunities to develop skills in molecular epidemiology, computational biology and infectious disease epidemiology. The comparative clinical training plan will enable the applicant to gain experience in infectious disease management among both human and animal populations under the guidance of infectious disease physicians and veterinary epidemiologists. The training environment at North Carolina State University is ideal for the applicants cross-disciplinary training goals, as the applicant also has access to resources and opportunities at Duke University and University of North Carolina-Chapel Hill.